Impact of active placebo controls on estimated drug effects in randomized trials: a meta-epidemiological study

In many clinical drug trials, patients and health care providers are not told who are allocated to the experimental drug and who are allocated to a similarly looking placebo control. This "blinding" procedure aims to protect against bias by ensuring an impartial assessment. Some patients may, however, experience noticeable side effects from the drug, eg, dry mouth or sedation, which can lead them to guess their allocated intervention. This is called loss of blinding or "unblinding." Active placebo controls are different from regular placebo controls because they contain ingredients that also imitate the side effects of the drug. We do not know whether this protects against bias from loss of blinding. Therefore, we wanted to assess if trials with active placebo controls yielded different results than similar trials with regular placebo controls. We found such trials by using meta-analyses of comparable trials with both types of placebo controls for various conditions, eg, pain and depression. With more than 100 meta-analyses, including approximately 1700 trials, this is the largest investigation of active placebo controls. We found that in trials using regular placebo controls, the experimental drug effect was slightly larger compared to similar trials with active placebo controls, on average (2%), but there was considerable variation between meta-analyses. The result could be a chance finding and, due to random variation, was compatible with both a 23% exaggeration and 24% underestimation of effect (when measured as odds ratio). In addition, the average may conceal relevant context-specific circumstances under which active placebo controls are more important or less important. We explored several potential circumstances without finding an explanation for the variation between meta-analyses. We conclude that it remains unclear if, and under which circumstances, active placebo controls are more reliable than standard placebo controls.